{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T21:30:44Z","timestamp":1791408644898,"version":"4.3.3"},"reference-count":71,"publisher":"Springer Science and Business Media LLC","issue":"8","license":[{"start":{"date-parts":[[2023,7,18]],"date-time":"2023-07-18T00:00:00Z","timestamp":1689638400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2023,7,18]],"date-time":"2023-07-18T00:00:00Z","timestamp":1689638400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Nat Med"],"published-print":{"date-parts":[[2023,8]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>\u03b1-Synuclein aggregates constitute the pathology of Lewy body (LB) disease. Little is known about the effects of LB pathology in preclinical (presymptomatic) individuals, either as isolated pathology or coexisting with Alzheimer\u2019s disease (AD) pathology (\u03b2-amyloid (A\u03b2) and tau). We examined the effects of LB pathology using a cerebrospinal fluid \u03b1-synuclein-seed amplification assay in 1,182\u2009cognitively and neurologically unimpaired participants from the BioFINDER study: 8% were LB positive, 26% A\u03b2 positive (13% of those were LB positive) and 16% tau positive. LB positivity occurred more often in the presence of A\u03b2 positivity but not tau positivity. LB pathology had independently negative effects on cross-sectional and longitudinal global cognition and memory and on longitudinal attention\/executive function. Tau had cognitive effects of a similar magnitude, but these were less pronounced for A\u03b2. Participants with both LB and AD (A\u03b2 and tau) pathology exhibited faster cognitive decline than those with only LB or AD pathology. LB, but not AD, pathology was associated with reduced sense of smell. Only LB-positive participants progressed to clinical LB disease over 10\u2009years. These results are important for individualized prognosis, recruitment and choice of outcome measures in preclinical LB disease trials, but also for the design of early AD trials because &gt;10% of individuals with preclinical AD have coexisting LB pathology.<\/jats:p>","DOI":"10.1038\/s41591-023-02450-0","type":"journal-article","created":{"date-parts":[[2023,7,18]],"date-time":"2023-07-18T13:03:00Z","timestamp":1689685380000},"page":"1971-1978","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":157,"title":["Cognitive effects of Lewy body pathology in clinically unimpaired individuals"],"prefix":"10.1038","volume":"29","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9267-1930","authenticated-orcid":false,"given":"Sebastian","family":"Palmqvist","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marcello","family":"Rossi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sara","family":"Hall","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Corinne","family":"Quadalti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Niklas","family":"Mattsson-Carlgren","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sofia","family":"Dellavalle","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pontus","family":"Tideman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joana B.","family":"Pereira","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6580-6721","authenticated-orcid":false,"given":"Maria H.","family":"Nilsson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Angela","family":"Mammana","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2869-8378","authenticated-orcid":false,"given":"Shorena","family":"Janelidze","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7702-7856","authenticated-orcid":false,"given":"Simone","family":"Baiardi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erik","family":"Stomrud","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9444-9524","authenticated-orcid":false,"given":"Piero","family":"Parchi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8467-7286","authenticated-orcid":false,"given":"Oskar","family":"Hansson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2023,7,18]]},"reference":[{"key":"2450_CR1","doi-asserted-by":"crossref","first-page":"157","DOI":"10.1016\/S1474-4422(19)30153-X","volume":"19","author":"JP Taylor","year":"2020","unstructured":"Taylor, J. P. et al. New evidence on the management of Lewy body dementia. Lancet Neurol. 19, 157\u2013169 (2020).","journal-title":"Lancet Neurol."},{"key":"2450_CR2","doi-asserted-by":"crossref","first-page":"954","DOI":"10.1038\/s41591-021-01382-x","volume":"27","author":"O Hansson","year":"2021","unstructured":"Hansson, O. Biomarkers for neurodegenerative diseases. Nat. Med. 27, 954\u2013963 (2021).","journal-title":"Nat. Med."},{"key":"2450_CR3","doi-asserted-by":"crossref","first-page":"864","DOI":"10.1016\/j.parkreldis.2013.05.010","volume":"19","author":"J Horvath","year":"2013","unstructured":"Horvath, J., Herrmann, F. R., Burkhard, P. R., Bouras, C. & Kovari, E. Neuropathology of dementia in a large cohort of patients with Parkinson\u2019s disease. Parkinsonism Relat. Disord. 19, 864\u2013868 (2013).","journal-title":"Parkinsonism Relat. Disord."},{"key":"2450_CR4","doi-asserted-by":"crossref","first-page":"745","DOI":"10.1136\/jnnp.51.6.745","volume":"51","author":"WR Gibb","year":"1988","unstructured":"Gibb, W. R. & Lees, A. J. The relevance of the Lewy body to the pathogenesis of idiopathic Parkinson\u2019s disease. J. Neurol. Neurosurg. Psychiatry 51, 745\u2013752 (1988).","journal-title":"J. Neurol. Neurosurg. Psychiatry"},{"key":"2450_CR5","doi-asserted-by":"crossref","first-page":"1100","DOI":"10.1212\/01.wnl.0000204179.88955.fa","volume":"66","author":"KJ Klos","year":"2006","unstructured":"Klos, K. J. et al. Alpha-synuclein pathology in the spinal cords of neurologically asymptomatic aged individuals. Neurology 66, 1100\u20131102 (2006).","journal-title":"Neurology"},{"key":"2450_CR6","doi-asserted-by":"crossref","first-page":"314","DOI":"10.1046\/j.0305-1846.2001.00342.x","volume":"27","author":"L Parkkinen","year":"2001","unstructured":"Parkkinen, L., Soininen, H., Laakso, M. & Alafuzoff, I. Alpha-synuclein pathology is highly dependent on the case selection. Neuropathol. Appl. Neurobiol. 27, 314\u2013325 (2001).","journal-title":"Neuropathol. Appl. Neurobiol."},{"key":"2450_CR7","doi-asserted-by":"crossref","first-page":"195","DOI":"10.1212\/WNL.0000000000200878","volume":"99","author":"G Bellomo","year":"2022","unstructured":"Bellomo, G. et al. alpha-Synuclein seed amplification assays for diagnosing synucleinopathies: the way forward. Neurology 99, 195\u2013205 (2022).","journal-title":"Neurology"},{"key":"2450_CR8","doi-asserted-by":"crossref","first-page":"90","DOI":"10.1186\/s40478-022-01388-7","volume":"10","author":"S Hall","year":"2022","unstructured":"Hall, S. et al. Performance of alphaSynuclein RT-QuIC in relation to neuropathological staging of Lewy body disease. Acta Neuropathol. Commun. 10, 90 (2022).","journal-title":"Acta Neuropathol. Commun."},{"key":"2450_CR9","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1186\/s40478-018-0508-2","volume":"6","author":"BR Groveman","year":"2018","unstructured":"Groveman, B. R. et al. Rapid and ultra-sensitive quantitation of disease-associated alpha-synuclein seeds in brain and cerebrospinal fluid by alphaSyn RT-QuIC. Acta Neuropathol. Commun. 6, 7 (2018).","journal-title":"Acta Neuropathol. Commun."},{"key":"2450_CR10","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1007\/s00401-020-02160-8","volume":"140","author":"M Rossi","year":"2020","unstructured":"Rossi, M. et al. Ultrasensitive RT-QuIC assay with high sensitivity and specificity for Lewy body-associated synucleinopathies. Acta Neuropathol. 140, 49\u201362 (2020).","journal-title":"Acta Neuropathol."},{"key":"2450_CR11","doi-asserted-by":"crossref","first-page":"407","DOI":"10.1016\/S1474-4422(23)00109-6","volume":"22","author":"A Siderowf","year":"2023","unstructured":"Siderowf, A. et al. Assessment of heterogeneity among participants in the Parkinson\u2019s Progression Markers Initiative cohort using alpha-synuclein seed amplification: a cross-sectional study. Lancet Neurol. 22, 407\u2013417 (2023).","journal-title":"Lancet Neurol."},{"key":"2450_CR12","doi-asserted-by":"crossref","first-page":"535","DOI":"10.1016\/j.jalz.2018.02.018","volume":"14","author":"CR Jack Jr.","year":"2018","unstructured":"Jack, C. R. Jr. et al. NIA-AA Research Framework: toward a biological definition of Alzheimer\u2019s disease. Alzheimers Dement. 14, 535\u2013562 (2018).","journal-title":"Alzheimers Dement."},{"key":"2450_CR13","doi-asserted-by":"crossref","first-page":"2381","DOI":"10.1038\/s41591-022-02049-x","volume":"28","author":"R Ossenkoppele","year":"2022","unstructured":"Ossenkoppele, R. et al. Amyloid and tau PET-positive cognitively unimpaired individuals are at high risk for future cognitive decline. Nat. Med. 28, 2381\u20132387 (2022).","journal-title":"Nat. Med."},{"key":"2450_CR14","doi-asserted-by":"crossref","first-page":"2771","DOI":"10.1093\/brain\/awab114","volume":"144","author":"D Berron","year":"2021","unstructured":"Berron, D. et al. Early stages of tau pathology and its associations with functional connectivity, atrophy and memory. Brain 144, 2771\u20132783 (2021).","journal-title":"Brain"},{"key":"2450_CR15","doi-asserted-by":"crossref","first-page":"e1525","DOI":"10.1212\/WNL.0000000000013299","volume":"98","author":"P Tideman","year":"2022","unstructured":"Tideman, P. et al. Association of beta-amyloid accumulation with executive function in adults with unimpaired cognition. Neurology 98, e1525\u2013e1533 (2022).","journal-title":"Neurology"},{"key":"2450_CR16","doi-asserted-by":"crossref","first-page":"871","DOI":"10.1038\/s41591-021-01309-6","volume":"27","author":"JW Vogel","year":"2021","unstructured":"Vogel, J. W. et al. Four distinct trajectories of tau deposition identified in Alzheimer\u2019s disease. Nat. Med. 27, 871\u2013881 (2021).","journal-title":"Nat. Med."},{"key":"2450_CR17","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1097\/WAD.0000000000000089","volume":"30","author":"A Economou","year":"2016","unstructured":"Economou, A., Routsis, C. & Papageorgiou, S. G. Episodic memory in Alzheimer disease, frontotemporal dementia, and dementia with Lewy bodies\/Parkinson disease dementia: disentangling retrieval from consolidation. Alzheimer Dis. Assoc. Disord. 30, 47\u201352 (2016).","journal-title":"Alzheimer Dis. Assoc. Disord."},{"key":"2450_CR18","doi-asserted-by":"crossref","first-page":"891","DOI":"10.1093\/jnen\/nlz080","volume":"78","author":"CH Adler","year":"2019","unstructured":"Adler, C. H. et al. Unified staging system for Lewy body disorders: clinicopathologic correlations and comparison to Braak staging. J. Neuropathol. Exp. Neurol. 78, 891\u2013899 (2019).","journal-title":"J. Neuropathol. Exp. Neurol."},{"key":"2450_CR19","doi-asserted-by":"crossref","first-page":"600","DOI":"10.1038\/nm0602-600","volume":"8","author":"J Xu","year":"2002","unstructured":"Xu, J. et al. Dopamine-dependent neurotoxicity of alpha-synuclein: a mechanism for selective neurodegeneration in Parkinson disease. Nat. Med. 8, 600\u2013606 (2002).","journal-title":"Nat. Med."},{"key":"2450_CR20","doi-asserted-by":"crossref","first-page":"321","DOI":"10.1038\/s41586-021-03948-8","volume":"598","author":"JY Lee","year":"2021","unstructured":"Lee, J. Y. et al. Dopamine facilitates associative memory encoding in the entorhinal cortex. Nature 598, 321\u2013326 (2021).","journal-title":"Nature"},{"key":"2450_CR21","doi-asserted-by":"crossref","DOI":"10.1038\/s41467-017-01150-x","volume":"8","author":"S Palmqvist","year":"2017","unstructured":"Palmqvist, S. et al. Earliest accumulation of beta-amyloid occurs within the default-mode network and concurrently affects brain connectivity. Nat. Commun. 8, 1214 (2017).","journal-title":"Nat. Commun."},{"key":"2450_CR22","first-page":"888","volume":"26","author":"A Hung","year":"2020","unstructured":"Hung, A., Schneider, M., Lopez, M. H. & McClellan, M. Preclinical Alzheimer disease drug development: early considerations based on Phase 3 clinical trials. J. Manag. Care Spec. Pharm. 26, 888\u2013900 (2020).","journal-title":"J. Manag. Care Spec. Pharm."},{"key":"2450_CR23","doi-asserted-by":"crossref","first-page":"1691","DOI":"10.1056\/NEJMoa2100708","volume":"384","author":"MA Mintun","year":"2021","unstructured":"Mintun, M. A. et al. Donanemab in early Alzheimer\u2019s disease. N. Engl. J. Med. 384, 1691\u20131704 (2021).","journal-title":"N. Engl. J. Med."},{"key":"2450_CR24","doi-asserted-by":"crossref","first-page":"80","DOI":"10.1186\/s13195-021-00813-8","volume":"13","author":"CJ Swanson","year":"2021","unstructured":"Swanson, C. J. et al. A randomized, double-blind, phase 2b proof-of-concept clinical trial in early Alzheimer\u2019s disease with lecanemab, an anti-Abeta protofibril antibody. Alzheimers Res. Ther. 13, 80 (2021).","journal-title":"Alzheimers Res. Ther."},{"key":"2450_CR25","doi-asserted-by":"crossref","first-page":"378","DOI":"10.1111\/j.1750-3639.2000.tb00269.x","volume":"10","author":"RL Hamilton","year":"2000","unstructured":"Hamilton, R. L. Lewy bodies in Alzheimer\u2019s disease: a neuropathological review of 145 cases using alpha-synuclein immunohistochemistry. Brain Pathol. 10, 378\u2013384 (2000).","journal-title":"Brain Pathol."},{"key":"2450_CR26","doi-asserted-by":"crossref","first-page":"156","DOI":"10.1093\/jnen\/64.2.156","volume":"64","author":"I Mikolaenko","year":"2005","unstructured":"Mikolaenko, I. et al. Alpha-synuclein lesions in normal aging, Parkinson disease, and Alzheimer disease: evidence from the Baltimore Longitudinal Study of Aging (BLSA). J. Neuropathol. Exp. Neurol. 64, 156\u2013162 (2005).","journal-title":"J. Neuropathol. Exp. Neurol."},{"key":"2450_CR27","doi-asserted-by":"crossref","first-page":"260","DOI":"10.1016\/j.neuron.2019.10.010","volume":"105","author":"F Bassil","year":"2020","unstructured":"Bassil, F. et al. Amyloid-beta (Abeta) plaques promote seeding and spreading of alpha-synuclein and tau in a mouse model of Lewy body disorders with Abeta pathology. Neuron 105, 260\u2013275 (2020).","journal-title":"Neuron"},{"key":"2450_CR28","doi-asserted-by":"crossref","first-page":"e1182","DOI":"10.1212\/WNL.0000000000006212","volume":"91","author":"DW Dickson","year":"2018","unstructured":"Dickson, D. W. et al. APOE epsilon4 is associated with severity of Lewy body pathology independent of Alzheimer pathology. Neurology 91, e1182\u2013e1195 (2018).","journal-title":"Neurology"},{"key":"2450_CR29","doi-asserted-by":"crossref","first-page":"509","DOI":"10.1212\/01.WNL.0000150892.81839.D1","volume":"64","author":"DW Tsuang","year":"2005","unstructured":"Tsuang, D. W. et al. Genetic association between the APOE*4 allele and Lewy bodies in Alzheimer disease. Neurology 64, 509\u2013513 (2005).","journal-title":"Neurology"},{"key":"2450_CR30","doi-asserted-by":"crossref","first-page":"353","DOI":"10.1002\/1531-8249(199903)45:3<353::AID-ANA11>3.0.CO;2-4","volume":"45","author":"CF Lippa","year":"1999","unstructured":"Lippa, C. F., Schmidt, M. L., Lee, V. M. & Trojanowski, J. Q. Antibodies to alpha-synuclein detect Lewy bodies in many Down\u2019s syndrome brains with Alzheimer\u2019s disease. Ann. Neurol. 45, 353\u2013357 (1999).","journal-title":"Ann. Neurol."},{"key":"2450_CR31","doi-asserted-by":"crossref","first-page":"1365","DOI":"10.1016\/S0002-9440(10)65722-7","volume":"153","author":"CF Lippa","year":"1998","unstructured":"Lippa, C. F. et al. Lewy bodies contain altered alpha-synuclein in brains of many familial Alzheimer\u2019s disease patients with mutations in presenilin and amyloid precursor protein genes. Am. J. Pathol. 153, 1365\u20131370 (1998).","journal-title":"Am. J. Pathol."},{"key":"2450_CR32","doi-asserted-by":"crossref","first-page":"7351","DOI":"10.3390\/molecules26237351","volume":"26","author":"M Upcott","year":"2021","unstructured":"Upcott, M., Chaprov, K. D. & Buchman, V. L. Toward a disease-modifying therapy of alpha-synucleinopathies: new molecules and new approaches came into the limelight. Molecules 26, 7351 (2021).","journal-title":"Molecules"},{"key":"2450_CR33","doi-asserted-by":"crossref","first-page":"567","DOI":"10.1002\/mds.29329","volume":"38","author":"L Concha-Marambio","year":"2023","unstructured":"Concha-Marambio, L. et al. Accurate detection of alpha-synuclein seeds in cerebrospinal fluid from isolated rapid eye movement sleep behavior disorder and patients with Parkinson\u2019s disease in the DeNovo Parkinson (DeNoPa) cohort. Mov. Disord. 38, 567\u2013578 (2023).","journal-title":"Mov. Disord."},{"key":"2450_CR34","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1186\/s40478-021-01282-8","volume":"9","author":"MJ Russo","year":"2021","unstructured":"Russo, M. J. et al. High diagnostic performance of independent alpha-synuclein seed amplification assays for detection of early Parkinson\u2019s disease. Acta Neuropathol. Commun. 9, 179 (2021).","journal-title":"Acta Neuropathol. Commun."},{"key":"2450_CR35","doi-asserted-by":"crossref","first-page":"3058","DOI":"10.1093\/brain\/awac115","volume":"145","author":"A Kluge","year":"2022","unstructured":"Kluge, A. et al. Detection of neuron-derived pathological alpha-synuclein in blood. Brain 145, 3058\u20133071 (2022).","journal-title":"Brain"},{"key":"2450_CR36","doi-asserted-by":"crossref","first-page":"2173","DOI":"10.1002\/mds.28651","volume":"36","author":"A Mammana","year":"2021","unstructured":"Mammana, A. et al. RT-QuIC detection of pathological alpha-synuclein in skin punches of patients with Lewy body disease. Mov. Disord. 36, 2173\u20132177 (2021).","journal-title":"Mov. Disord."},{"key":"2450_CR37","first-page":"1","volume":"78","author":"Z Wang","year":"2020","unstructured":"Wang, Z. et al. Skin alpha-synuclein aggregation seeding activity as a novel biomarker for Parkinson disease. JAMA Neurol. 78, 1\u201311 (2020).","journal-title":"JAMA Neurol."},{"key":"2450_CR38","doi-asserted-by":"crossref","first-page":"642","DOI":"10.1002\/mds.22971","volume":"25","author":"CH Adler","year":"2010","unstructured":"Adler, C. H. et al. Incidental Lewy body disease: clinical comparison to a control cohort. Mov. Disord. 25, 642\u2013646 (2010).","journal-title":"Mov. Disord."},{"key":"2450_CR39","doi-asserted-by":"crossref","first-page":"e0231720","DOI":"10.1371\/journal.pone.0231720","volume":"15","author":"TG Beach","year":"2020","unstructured":"Beach, T. G. et al. Severe hyposmia distinguishes neuropathologically confirmed dementia with Lewy bodies from Alzheimer\u2019s disease dementia. PLoS ONE 15, e0231720 (2020).","journal-title":"PLoS ONE"},{"key":"2450_CR40","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1590\/1980-57642018dn12-020004","volume":"12","author":"MME Silva","year":"2018","unstructured":"Silva, M. M. E., Mercer, P. B. S., Witt, M. C. Z. & Pessoa, R. R. Olfactory dysfunction in Alzheimer\u2019s disease Systematic review and meta-analysis. Dement. Neuropsychol. 12, 123\u2013132 (2018).","journal-title":"Dement. Neuropsychol."},{"key":"2450_CR41","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/nm.4269","volume":"23","author":"YC Wong","year":"2017","unstructured":"Wong, Y. C. & Krainc, D. Alpha-synuclein toxicity in neurodegeneration: mechanism and therapeutic strategies. Nat. Med. 23, 1\u201313 (2017).","journal-title":"Nat. Med."},{"key":"2450_CR42","doi-asserted-by":"crossref","first-page":"743","DOI":"10.1212\/WNL.0000000000009323","volume":"94","author":"IG McKeith","year":"2020","unstructured":"McKeith, I. G. et al. Research criteria for the diagnosis of prodromal dementia with Lewy bodies. Neurology 94, 743\u2013755 (2020).","journal-title":"Neurology"},{"key":"2450_CR43","doi-asserted-by":"crossref","first-page":"1773","DOI":"10.1212\/WNL.0000000000004567","volume":"89","author":"WD Brenowitz","year":"2017","unstructured":"Brenowitz, W. D. et al. Mixed neuropathologies and associations with domain-specific cognitive decline. Neurology 89, 1773\u20131781 (2017).","journal-title":"Neurology"},{"key":"2450_CR44","doi-asserted-by":"crossref","first-page":"1243","DOI":"10.3233\/JAD-201187","volume":"80","author":"SG Ryman","year":"2021","unstructured":"Ryman, S. G. et al. Cognition at each stage of Lewy body disease with co-occurring Alzheimer\u2019s disease pathology. J. Alzheimers Dis. 80, 1243\u20131256 (2021).","journal-title":"J. Alzheimers Dis."},{"key":"2450_CR45","doi-asserted-by":"crossref","first-page":"484","DOI":"10.1016\/S1474-4422(21)00066-1","volume":"20","author":"B Dubois","year":"2021","unstructured":"Dubois, B. et al. Clinical diagnosis of Alzheimer\u2019s disease: recommendations of the International Working Group. Lancet Neurol. 20, 484\u2013496 (2021).","journal-title":"Lancet Neurol."},{"key":"2450_CR46","doi-asserted-by":"crossref","first-page":"772","DOI":"10.1001\/jama.2020.12134","volume":"324","author":"S Palmqvist","year":"2020","unstructured":"Palmqvist, S. et al. Discriminative accuracy of plasma phospho-tau217 for Alzheimer disease vs other neurodegenerative disorders. JAMA 324, 772\u2013781 (2020).","journal-title":"JAMA"},{"key":"2450_CR47","doi-asserted-by":"crossref","DOI":"10.1038\/s41467-020-15436-0","volume":"11","author":"S Janelidze","year":"2020","unstructured":"Janelidze, S. et al. Cerebrospinal fluid p-tau217 performs better than p-tau181 as a biomarker of Alzheimer\u2019s disease. Nat. Commun. 11, 1683 (2020).","journal-title":"Nat. Commun."},{"key":"2450_CR48","doi-asserted-by":"crossref","first-page":"913","DOI":"10.1002\/mds.25037","volume":"27","author":"RB Postuma","year":"2012","unstructured":"Postuma, R. B. et al. A single-question screen for rapid eye movement sleep behavior disorder: a multicenter validation study. Mov. Disord. 27, 913\u2013916 (2012).","journal-title":"Mov. Disord."},{"key":"2450_CR49","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1001\/archneur.56.1.33","volume":"56","author":"DJ Gelb","year":"1999","unstructured":"Gelb, D. J., Oliver, E. & Gilman, S. Diagnostic criteria for Parkinson disease. Arch. Neurol. 56, 33\u201339 (1999).","journal-title":"Arch. Neurol."},{"key":"2450_CR50","doi-asserted-by":"crossref","first-page":"1863","DOI":"10.1212\/01.wnl.0000187889.17253.b1","volume":"65","author":"IG McKeith","year":"2005","unstructured":"McKeith, I. G. et al. Diagnosis and management of dementia with Lewy bodies: third report of the DLB Consortium. Neurology 65, 1863\u20131872 (2005).","journal-title":"Neurology"},{"key":"2450_CR51","doi-asserted-by":"crossref","first-page":"1060","DOI":"10.1001\/jamaneurol.2019.1632","volume":"76","author":"S Palmqvist","year":"2019","unstructured":"Palmqvist, S. et al. Performance of fully automated plasma assays as screening tests for Alzheimer disease-related beta-amyloid status. JAMA Neurol. 76, 1060\u20131069 (2019).","journal-title":"JAMA Neurol."},{"key":"2450_CR52","doi-asserted-by":"crossref","first-page":"1034","DOI":"10.1038\/s41591-021-01348-z","volume":"27","author":"S Palmqvist","year":"2021","unstructured":"Palmqvist, S. et al. Prediction of future Alzheimer\u2019s disease dementia using plasma phospho-tau combined with other accessible measures. Nat. Med. 27, 1034\u20131042 (2021).","journal-title":"Nat. Med."},{"key":"2450_CR53","doi-asserted-by":"crossref","first-page":"1204","DOI":"10.1002\/alz.12751","volume":"19","author":"S Palmqvist","year":"2022","unstructured":"Palmqvist, S. et al. An accurate fully automated panel of plasma biomarkers for Alzheimer\u2019s disease. Alzheimers Dement. 19, 1204\u20131215 (2022).","journal-title":"Alzheimers Dement."},{"key":"2450_CR54","doi-asserted-by":"crossref","first-page":"1591","DOI":"10.1002\/mds.26424","volume":"30","author":"RB Postuma","year":"2015","unstructured":"Postuma, R. B. et al. MDS clinical diagnostic criteria for Parkinson\u2019s disease. Mov. Disord. 30, 1591\u20131601 (2015).","journal-title":"Mov. Disord."},{"key":"2450_CR55","doi-asserted-by":"crossref","first-page":"1191","DOI":"10.3233\/JAD-191191","volume":"75","author":"F Petrazzuoli","year":"2020","unstructured":"Petrazzuoli, F. et al. Brief cognitive tests used in primary care cannot accurately differentiate mild cognitive impairment from subjective cognitive decline. J. Alzheimers Dis. 75, 1191\u20131201 (2020).","journal-title":"J. Alzheimers Dis."},{"key":"2450_CR56","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1186\/s13195-020-00592-8","volume":"12","author":"E Borland","year":"2020","unstructured":"Borland, E., Stomrud, E., van Westen, D., Hansson, O. & Palmqvist, S. The age-related effect on cognitive performance in cognitively healthy elderly is mainly caused by underlying AD pathology or cerebrovascular lesions: implications for cutoffs regarding cognitive impairment. Alzheimers Res. Ther. 12, 30 (2020).","journal-title":"Alzheimers Res. Ther."},{"key":"2450_CR57","doi-asserted-by":"crossref","first-page":"893","DOI":"10.3233\/JAD-170203","volume":"59","author":"E Borland","year":"2017","unstructured":"Borland, E. et al. The Montreal Cognitive Assessment: normative data from a large Swedish population-based cohort. J. Alzheimers Dis. 59, 893\u2013901 (2017).","journal-title":"J. Alzheimers Dis."},{"key":"2450_CR58","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1186\/alzrt94","volume":"3","author":"SD Shirk","year":"2011","unstructured":"Shirk, S. D. et al. A web-based normative calculator for the uniform data set (UDS) neuropsychological test battery. Alzheimers Res. Ther. 3, 32 (2011).","journal-title":"Alzheimers Res. Ther."},{"key":"2450_CR59","doi-asserted-by":"crossref","first-page":"668","DOI":"10.1016\/j.trci.2017.10.004","volume":"3","author":"KV Papp","year":"2017","unstructured":"Papp, K. V., Rentz, D. M., Orlovsky, I., Sperling, R. A. & Mormino, E. C. Optimizing the preclinical Alzheimer\u2019s cognitive composite with semantic processing: the PACC5. Alzheimers Dement. (N.Y.) 3, 668\u2013677 (2017).","journal-title":"Alzheimers Dement. (N.Y.)"},{"key":"2450_CR60","doi-asserted-by":"crossref","first-page":"1356","DOI":"10.1176\/ajp.141.11.1356","volume":"141","author":"WG Rosen","year":"1984","unstructured":"Rosen, W. G., Mohs, R. C. & Davis, K. L. A new rating scale for Alzheimer\u2019s disease. Am. J. Psychiatry 141, 1356\u20131364 (1984).","journal-title":"Am. J. Psychiatry"},{"key":"2450_CR61","doi-asserted-by":"crossref","first-page":"e322","DOI":"10.1212\/WNL.0000000000007831","volume":"93","author":"PS Insel","year":"2019","unstructured":"Insel, P. S. et al. Determining clinically meaningful decline in preclinical Alzheimer disease. Neurology 93, e322\u2013e333 (2019).","journal-title":"Neurology"},{"key":"2450_CR62","doi-asserted-by":"crossref","first-page":"46","DOI":"10.1186\/s13195-022-00990-0","volume":"14","author":"A Pichet Binette","year":"2022","unstructured":"Pichet Binette, A. et al. Combining plasma phospho-tau and accessible measures to evaluate progression to Alzheimer\u2019s dementia in mild cognitive impairment patients. Alzheimers Res. Ther. 14, 46 (2022).","journal-title":"Alzheimers Res. Ther."},{"key":"2450_CR63","unstructured":"Smith, A. Symbol Digit Modalities Test (Western Psychological Services, 1991)."},{"key":"2450_CR64","doi-asserted-by":"crossref","first-page":"189","DOI":"10.1016\/0022-3956(75)90026-6","volume":"12","author":"MF Folstein","year":"1975","unstructured":"Folstein, M. F., Folstein, S. E. & McHugh, P. R. \u2018Mini-mental state\u2019. A practical method for grading the cognitive state of patients for the clinician. J. Psychiatr. Res. 12, 189\u2013198 (1975).","journal-title":"J. Psychiatr. Res."},{"key":"2450_CR65","doi-asserted-by":"crossref","first-page":"353","DOI":"10.1097\/00005537-199603000-00021","volume":"106","author":"RL Doty","year":"1996","unstructured":"Doty, R. L., Marcus, A. & Lee, W. W. Development of the 12-item Cross-Cultural Smell Identification Test (CC-SIT). Laryngoscope 106, 353\u2013356 (1996).","journal-title":"Laryngoscope"},{"key":"2450_CR66","doi-asserted-by":"crossref","first-page":"1529","DOI":"10.1002\/lary.25173","volume":"125","author":"E Cantone","year":"2015","unstructured":"Cantone, E., Maione, N., Di Rubbo, V., Esposito, F. & Iengo, M. Olfactory performance after crenotherapy in chronic rhinosinusitis in the elderly. Laryngoscope 125, 1529\u20131534 (2015).","journal-title":"Laryngoscope"},{"key":"2450_CR67","doi-asserted-by":"crossref","unstructured":"\u00c5strand, R., Rolstad, S. & Wallin, A. Cognitive Impairment Questionnaire (CIMP-QUEST): reported topographic symptoms in MCI and dementia. Acta Neurol. Scand. 121, 384\u2013391 (2010).","DOI":"10.1111\/j.1600-0404.2009.01312.x"},{"key":"2450_CR68","unstructured":"Fahn S. in Recent Developments in Parkinson\u2019s Disease (eds Marsden, C. D. et al.) 153\u2013163 (Macmillan Healthcare Information, 1987)."},{"key":"2450_CR69","doi-asserted-by":"crossref","first-page":"1","DOI":"10.18637\/jss.v032.i06","volume":"32","author":"T Benaglia","year":"2009","unstructured":"Benaglia, T., Chauveau, D., Hunter, D. R. & Young, D. S. mixtools: an R Package for analyzing finite mixture models. J. Stat. Softw. 32, 1\u201329 (2009).","journal-title":"J. Stat. Softw."},{"key":"2450_CR70","doi-asserted-by":"crossref","first-page":"1492","DOI":"10.1001\/jamaneurol.2017.2814","volume":"74","author":"S Janelidze","year":"2017","unstructured":"Janelidze, S. et al. Concordance between different amyloid immunoassays and visual amyloid positron emission tomographic assessment. JAMA Neurol. 74, 1492\u20131501 (2017).","journal-title":"JAMA Neurol."},{"key":"2450_CR71","doi-asserted-by":"crossref","first-page":"e930","DOI":"10.1212\/WNL.0000000000012438","volume":"97","author":"M Rossi","year":"2021","unstructured":"Rossi, M. et al. Diagnostic value of the CSF alpha-synuclein real-time quaking-induced conversion assay at the prodromal MCI stage of dementia with Lewy bodies. Neurology 97, e930\u2013e940 (2021).","journal-title":"Neurology"}],"container-title":["Nature Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41591-023-02450-0.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41591-023-02450-0","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41591-023-02450-0.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,8,15]],"date-time":"2023-08-15T14:15:14Z","timestamp":1692108914000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41591-023-02450-0"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,7,18]]},"references-count":71,"journal-issue":{"issue":"8","published-print":{"date-parts":[[2023,8]]}},"alternative-id":["2450"],"URL":"https:\/\/doi.org\/10.1038\/s41591-023-02450-0","relation":{},"ISSN":["1078-8956","1546-170X"],"issn-type":[{"value":"1078-8956","type":"print"},{"value":"1546-170X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,7,18]]},"assertion":[{"value":"21 January 2023","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"8 June 2023","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"18 July 2023","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"None of the authors have any financial interest in the \u03b1-syn SAA test. S.P. has acquired research support (for the institution) from ki elements\/Alzheimer Drug Discoveries Foundation. In the past 2\u2009years he has received consultancy\/speaker fees from Bioartic, Biogen, Eli Lilly and Roche. O.H. has acquired research support (for the institution) from ADx, AVID Radiopharmaceuticals, Biogen, Eli Lilly, Eisai, Fujirebio, GE Healthcare, Pfizer and Roche. In the past 2\u2009years he has received consultancy\/speaker fees from AC Immune, Amylyx, Alzpath, BioArctic, Biogen, Cerveau, Eisai, Eli Lilly, Fujirebio, Genentech, Novartis, Novo Nordisk, Roche and Siemens. The remaining authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}]}}